JPS61172858A - Production of prostaglandin e1 derivative - Google Patents

Abstract

PURPOSE:To produce the titled substance useful as pharmaceuticals, in high efficiency, by reducing the 7,8-double bond of a DELTA<7>-prostaglandin E1 derivative selectively with an organotin hydride compound organic of a 0-valent Pd catalyst. CONSTITUTION:The objective compound of formula III can be produced by reducing the DELTA<7>-prostaglandin E1 derivative of formula I (R<1> is H, alkyl, phenyl, cycloalkyl, etc.; R<2> and R<3> are H, tri(hydrocarbon)silyl or form acetal bond together with O atom of OH group; R<4> is H, CH3 or vinyl; R<5> is alkyl, phenyl, cycloalkyl, etc.; A is CH2 or S; B is single bond or CH2; the expression of formula II represents the existence the existence of 7Z-isomer, 7E-isomer or their mixture at an arbitrary ratio) with an organotin hydride compound in the presence of a 0-valent Pd catalyst (preferably a Pd complex having methyldiphenylphosphine, etc., as the ligand).

Description

DETAILED DESCRIPTION OF THE INVENTION Field of Industrial Application The present invention relates to a novel method for producing prostaglandin E derivatives useful as pharmaceuticals.

More details: Δ7-Prostaglandin E.

Related to a method for producing a staglandin E derivative useful as a pharmaceutical by reducing the double bond at position 7.8 of the derivative with an organotin hydride compound in the presence of a zero-valent radium catalyst. Technology〉 Prostaglandin E, derivatives inhibit platelet aggregation,
It is a compound that has physiological effects such as vasodilatory, antiulcer, and immunosuppressive effects, and is currently being applied clinically.

Conventionally, as a method for obtaining the prostaglandin E1 derivative using the Δ1-prostaglandin E derivative as a starting material, the Δ77-brostaglandin E. l conductor α.
A reduction reaction is carried out via a radical reaction with an organotin hydride compound such as tributyltin hydride in the presence of a radical initiator such as α′-azobisisobutyronitrile or bis-t-butyl peroxide, It had accomplished its purpose. In particular, the difficulty of this reaction is that the Δ7-prostaglandin island derivative, which is not very stable to heat, is subjected to a radical reduction reaction at high temperature.In particular, in formula CI) below, A is sulfur Atom compound Δ7-5-thiapuxtaglandin E.

Derivatives can readily decompose to form allyl sulfide radicals as their reaction intermediates, often giving undesirable by-products. Furthermore, there were practical problems such as the need to use a large excess amount of the organic tin hydride compound in order to complete the reaction.

<Purpose of the Invention> As a result of intensive research by the present inventors to find a more profitable chemical synthesis method for producing prostaglandin E and its derivatives from Δ11-brostaglanshiff E and I conductors, we found that ΔD-brostaglandin By subjecting the E1 derivative to a non-radical conjugate reduction reaction using an organic tin hydride compound in the presence of a zero-valent palladium catalyst, the conjugate reduction reaction can be carried out efficiently and in high yield at a lower temperature. This is what we have discovered and arrived at the present invention.

Therefore, the object of the present invention is to selectively reduce the double bond at position 7.8 of the Δhoooprostaglandin sushi crocodile conductor, and produce prostaglandin E and derivatives useful as pharmaceuticals in an industrially advantageous manner. , and moreover, it is possible to get a good moving vehicle.

<Structure and Effects of the Invention> The production method of the present invention provides Δ7-buxtaglandin E, a derivative represented by the following formula [1],
This is a method for producing prostaglandin E, a derivative represented by the following formula C.

As described above, the production method of the present invention uses Δ1-prostaglandin E, a derivative represented by the above formula CI) having a double bond at the 7.8-position as a starting material, and selectively reduces the double bond. Prostaglandin E and its derivatives are produced.

In the above formula [■], RI is a hydrogen atom, a C1-C1° alkyl group, a substituted or unsubstituted phenyl group, a substituted or unsubstituted C8-C,6 cycloalkyl group, or a substituted or unsubstituted phenyl CC1-Ct ) The alkyl group was expressed.

C, -C,. Examples of the alkyl group include methyl,
Ethyl, n-propyl, 1so-propyl, n-butyl, 5ac-butyl, tart-butyl, n
Examples include linear or branched ones such as -pentyl, n-hexyl, n-heptyl, n-octyl, n-nonyl, and n-decyl.

Examples of substituents for directly substituted or unsubstituted phenyl groups include halogen atoms, hydroxy groups, C* to C, acyloxy groups, and C1 to C4 which may be substituted with halogen atoms.
C8 which may be substituted with an alkyl group or a halogen atom
-C4 alkoxy group, nitrile group, carboxyl group, (C1-C6) alfkidicarbonyl group, etc. are preferred.

The halogen atom is preferably fluorine, chlorine or bromine, particularly fluorine or chlorine.

Examples of the C3-C acyloxy group include acetoxy,
Propionyloxy, n-butyryloxy, 1so
-butyryloxy, n-valeryloxy, 1so-
Mention may be made of valeryloxy, carbyloxy, enantyloxy or benzoyloxy.

C1-〇, alkyl group which may be substituted with ky, include methyl, ethyl, n-propyl, 1s
o-propyl, n-butyl, lyalomethyl, dicIC
Preferred examples include I-methyl and trifluoromethyl. Examples of the C3-C, alkoxy group which may be substituted with halogen include methoxy.

Ethoxy, n-propoxy, 1so-propoxy,
Preferred examples include n-butoxy, ria-lomethoxy, di-a-lomethoxy, and trifluoromethoxy. (CI~゛C.)Alkoxycarbonyl groups include, for example, methoxycarbonyl and ethoxycarbonyl.

Examples include phthoxycarbonyl, hexyloxycarbonyl, and the like.

The substituted phenyl group can have 1 to 3, preferably 1 substituent as described above.

The substituted or unsubstituted C3-C7° cycloalkyl group may be a saturated or unsaturated C1-C,OS, preferably C,-c, substituted with the same substituent as mentioned above or unsubstituted. Particularly preferred hcs groups include cyclopropyl/cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, cyclodecyl, and the like.

Examples of substituted or unsubstituted phenyl (CI-Ct)alkyl groups include nopenzyl, α-7enethyl, and β-phenethyl, in which the phenyl group is substituted with the same substituents as mentioned above, or unsubstituted.

R1 is preferably a hydrogen atom or a C, -0IG alkyl group.

R' and R3 are the same or different and are a group that forms an acetal bond with a hydrogen atom, a (Ct-Ct) hydrocarbon silyl group, or an oxygen atom of a hydroxyl group.

) +7 (C, ~C2) hydrocarbon silyl group,
For example, trimethylsilyl, triethylsilyl.

Tri(Ct-C4) such as t-butyldimethylsilyl group
Preferable examples include alkylsilyl, diphenyl(C3-C4)alkylsilyl such as t-phthyldiphenylsilyl, phenylCC1-C4)alkylsilyl such as dimethylphenylsilyl, and tribenzylsilyl.

An example of a group that forms an acetal bond with the oxygen atom of a hydroxyl group is methoxymethyl.

1-ethoxyethyl, 2-methoxy-2-propylene,
2-Ethoxy-2-propyl, (2-methoxyethoxy)methyl, benzyloxymethyl, 2-tetrahydropyranyl, 2-tetrahydrofuranyl or 6,6-dimethyl-3-oxa-2-oxobicyclo(3,1,0 ) hex-4-yl group. Among these, 2-tetrahydropyranyl, 2-tetrahydroafuranyl, 1-ethoxyethyl, 2-methoxy-2-propyl, (2-methoxyethoxy)methyl or Fi6.6-dimethe-3-oxa-2-oxobicyclo (3,1,0)
Particularly preferred is the hex-4-yl group.

Among these, R1 or R1 is a hydrogen atom, a tri(C1-C4) alkylsilyl group, or a diphenyl (C, -
C4) alkylsilyl group, phenyldi(C1-C4)alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahytoa7ranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy ) Methyl group or 6,6-dimethyl-3-oxa-2-oquin-bisicH(3,1,0)hex-4-yl group is preferred.

In the above formula m, R4 represents a hydrogen atom, a methyl group or a vinyl group.

In the above formula CI], R' is a linear or branched C8-C alkyl group which may contain an oxygen atom; an optionally substituted phenyl group, phenoxy group or a C5-C
C1o cycloalkyl group; or C1-0, alkyl group, optionally substituted phenyl group, phenoxy group, straight chain or branched C, ~CbCs alkyl substituted with C8-C10 cycloalkyl group; base

Straight chain or branched chain Cs” which may contain an oxygen atom
Cs alkyl group: 2-methoxyethyl, 2-ethoxyethyl, propyl.

Butyl, pentyl, hexyl, heptyl, octyl, l
-Methylbutyl, 2-methylbutyl, 2-°methylhexyl, 2-methyl-2-hexyl, 2-hexyl, 1.
1-dimethylpentyl group, preferably R2-methoxyethyl.

Butyl, pentyl, hexyl, @- or ■)-2-
Methyl-hexyl, 1-methylbutyl groups, particularly preferably butyl and pentyl groups can be mentioned.

The optionally substituted phenyl group and phenoxy group may be substituted with the substituents listed as substituents for the H+ substituted phenyl group. Further, the optionally substituted C3-C, cycloalkyl group may be substituted with the same substituents as mentioned above, or unsubstituted saturated or unsaturated C8-. , preferably C4'''-C
? +Particularly preferred cycloalkyl group 1 of FiC, C, Examples include cyclopropyl, cyclopentyl, cyclohexyl, cyclohexenyl, cycloheptyl, cyclooctyl, and cyclodecyl groups.

C, -C, alkoxy group, optionally substituted phenyl group, phenoxy group also L < dcs~C9゜ Straight chain or branched chain C, -C substituted with cycloalkyl group
, Among the alkyl groups, examples of the 01-C6 alkoxy group include methoxy, ethoxy, propoxy, impropoxy, butoxy, t-butoxy, and hexyloxy groups, and optionally substituted phenyl and phenoxy groups include can be preferably mentioned as is. C1-〇. The above-mentioned cycloalkyl groups can be preferably mentioned as they are, and examples of straight-chain or branched C1-Cs alkyl groups include methyl and ethyl.

Propyl, 1so-propyl, butyl, 1so-butyl, 5e(-butyl, t-butyl, pentyl, etc.) can be mentioned, and the substituent may be bonded to any position thereof.

In the above formula [13], A represents a methylene group or a sulfur atom. A represents a methylene group.

When the above formula (1) is expressed by the following formula (1-1), Δ7-prostaglandin El! II means conductor, and A is sulfur! When representing a child, the above formula (1) is replaced by 5-thia Δ7-prostaglandin &
ml means conductor.

In the above formula (1), BF'i represents a single bond or a methylene group. When B represents a single bond, the above formula [I] is
It means a Δ7-prostaglandin EI derivative represented by the following formula [T-3], and when B represents a methylene group, the above formula (1) is
15-deoxy-16-hydroxy-Δ-prostaglandin E represented by the following formula [1-4], meaning a derivative @ the above formula (1) ([l-13,Cl-2), (1- 3),
and CI-4), the symbol ^ indicates that the stereochemistry of the double bond is 7z form, 71 form, or 7z form and 7E form coexist in any proportion.

Also, the above formula [1) ((1-D, Cl-23, (1-a)
, and (including r-4), the configuration of the substituent bonded to the cyclobentenone ring is the same as that of natural prostaglandin E. The stereoisomer represented by the formula % formula % and its mirror form the following formula CI
) @nt It also includes stereoisomers represented by @nt or a mixture of both in any proportion.

Also, since the carbons substituted by OR'', R' and R5 are asymmetric carbons, there are two types of optical isomers, but any of the optical isomers or a mixture of them in any proportion can be used. Δ7-prostaglandin E, which is the starting material of the present invention,
The derivative was protected (optically active) 4 as shown in the reaction formula below by a method separately proposed by the present inventors (see, for example, JP-A-58-83670).
7-Hydroxyprostaglandin E, an aldol condensate of an enolate intermediate obtained by conjugate addition of an organocopper compound to -hydroxy-2-cyclobentenone, can be easily obtained by subjecting the derivative to a dehydration reaction. It will be done.

[Δ7 represented by the above formula [1] which is the starting material of the present invention
Preferred specific examples of -buta staglandin E and derivatives include the compounds shown below. Note that prostaglandin E is abbreviated as PGE. In addition, both compounds have geometric isomers of 7z form and 7E form, but both of them are similarly used as the starting material (1) of the present invention.
△? -PGE.

(2) 15-methyl-Δ’ PG& (3) 15-vinyl-Δ'-PGE.

(4) 20-methyl-Δ1-PGE.

(5) 20-ethyl-Δff-PG island (6) 17(S), 20-dil f rou Δ'
-PGE1(7)1'r@,2o-dimethyl-8-
PGg.

(9) 16-methyl-Δ'-PGE.

(9) 16, 16-dimenalu Δ'-PGE.

(10) 16,17.18,19.20-pentanol-
15-CyclobenylΔ'-PGE.

(11) 16.17.18,19.20-pentanol-15-cyclohexyl-Δ' PGE+ (12)
17.18.19.20-tetrano-I-16-cyclohexyl-Δ? -PGE.

(13) 18-oxa-Δfu PGE+ (14) 1
7,18,19,20-tetratrue-16-phenyl-Δ? -PGE.

(15) 17.18, 19.20- Tet
Ranol-16-phenoxy-Δ'-PGE.

(16) 15-deoxy-16-hydroxy-Δ'-P
G.E.

(17) 15-deoxy-16-hydroxy-16
-Methyl-Δ'-PGE1 (18) 15-deoxy-16-hydroxy-16-vinyl-ΔD-PGE.

(19) 15-deoxy-16-hydroxy-20-methyl-Δ'-PGE.

(20) 15-deoxy-16-hydroxy-17,1
8,19,20-tetratrue 16-cyclohexylΔ'-PGE.

(21) 15-deoxy-16-hydroxy-17
,18,19,20-tetratrue-16-phenyl-Δ
'-P(J.

(22) 15-deoxy-16-hydroxy-17,2
0-dimethyl-Δ'-PGE.

(23) 5-thia Δ'-PG of (1) to (22)
E, derivative (24) Enantiomer (25) of the compounds of (1) to (23) (25) Methyl ester of (1) to (24) (
26) Ethyl ester of (1) to (24) (27)
Hydroxyl groups (11-position and 15-position) of compounds (1) to (26)
Examples include, but are not limited to, compounds in which the 2-tetrahydropyranyl group (or the 16th position) is protected by a 2-tetrahydropyranyl group/or a Fit-7'-methyldimethylsilyl group. Also included are 15-shrimp forms (also #i16-shrimp forms) of the compounds (1) to (27) and their enantiomers.

The method of the present invention is to selectively reduce the double bonds at positions 7 and 8 of the above formula (1) to lead to the a-stag 2-injin E derivative represented by the above formula [■]. That is, the above formula [
The corresponding prostaglandin E + N conductor represented by the above formula [■] is easily prepared by reacting the derivative of Δhoooprostaglandin E represented by [1] with an organotin hydride compound in the presence of a zero-valent palladium catalyst. can be obtained.

The zero-valent palladium catalyst used in the above reaction includes zero-valent palladium itself, or one that forms a complex with an appropriate ligand. A zero-valent palladium complex with improved solubility is preferred. Ligand number of such zero-valent palladium catalyst #: t1,2
-diphenylphosphinoethane, methyldiphenylphosphine, triphenylphosphine, dibenzylideneacetone, etc.) 17 Phenylphosphine is particularly preferred, and the zero-valent palladium complex coordinated with the ligand is tetrakis (Triphenylphosphine) palladium <0> can be mentioned.

Further, even if the catalyst is reduced in the reaction system to produce a zero-valent palladium catalyst, the reaction will proceed, which is preferable and can be carried out according to the present invention.

The amount of the zero-valent palladium catalyst used is related to its catalytic ability, but it is usually 10 mol % to 0. It is sufficient to use an amount of 0.1 mol% for O1 mol%, preferably tL<U3 mol%.

Examples of organic tin hydride compounds include diptyltin dihydride, tributyltin hydride, tributyltin deuteride, triphenyltin hydride, and tributyltin hydride, which is easily available, is particularly preferred. The amount used varies depending on its reactivity, but is usually from 1 equivalent to 1000
The amount used is preferably from 1 equivalent to 100 equivalents, particularly preferably from 2 equivalents to 10 equivalents. Reaction solvents may be used as necessary, and usually benzene, tetrahydrofuran, chloroform, dioxane, etc. are used, but the reaction will proceed even without a solvent, and if the reaction system is homogeneous, it is better to use a reaction solvent without a solvent. preferable.

The reaction temperature is 0°C to 100°C, preferably 20°C to 60°C, and the reaction time is 1 to 100°C.
Although the reaction temperature and reaction time usually vary depending on the catalyst and reducing agent used, gas chromatography, liquid atomography,
It is effective to carry out the reaction while monitoring it using analytical means such as thin layer chromatography.

After the completion of the reaction, the prostaglandin E1 derivative represented by the above formula [11] is separated using conventional methods such as mild water treatment, extraction, washing, drying, D separation, concentration, and then chromatography. It can be separated and purified.

In this way, prostaglandin E and derivatives represented by the above formula [■] are isolated, and from the above formula (1) nat and the above formula [1] ent, respectively, the corresponding prostaglandin E and tR derivatives, which are the following formula (1) ) nat, a prostaglandin E derivative having the configuration represented by the following formula ([,] ant) is obtained as the main product.

A specific example of the prostaglandif G represented by the above formula [I[) and the derivative is Δ7-puxtaglandin E represented by the above formula (1).

Compounds corresponding to specific examples of derivatives can be mentioned as they are.

Thus, according to the present invention, Δ2-prostaglandin E can be produced in high yields under mild conditions while avoiding radical reactions.
A useful synthetic method for obtaining derivatives has now been completed.

The present invention will be explained below using examples.

Synthesis of Example 1 Δ Hoop Prostaglandin E, Methyl Ester 11.1
5-bis(t-butyldimethylsilyl)ether (55
, 4g, 93.3 mmol) with tetrakis (
) Riphenylphosphine) Palladium(0) (538
rz, 0.467 mmol) and stirred at room temperature under a nitrogen atmosphere, tributyltin hydride (8
1.5 g (1280 mmol) was gradually added dropwise over 12 hours. After the dropwise addition, 100 - of a saturated ammonium chloride aqueous solution was added, and after stirring for 15 minutes, hexane (300 dX
3) After extraction, the obtained organic layer was washed with brine. The separated organic layer was dried over anhydrous magnesium sulfate, separated by a, and concentrated to obtain 165 g of a crude product. This material was used for silica gel column chromatography (silica gel 1 kg;
Prostaglandin E, methyl ester 11.1
5-bis(t-butyldimethylsilyl)ether (49
, 5g183.0 mmo189%) was obtained.

IR (neat): 1743, 1253, 835, 77
4cm” NMR (δ-in CDCjs): 0 to 0.2 (m, 12H), 0.89 (s, 18H),
0.7-1.1 (m.

3H), 1.1-3.0 (m, 24H), 3.70 (s
, 3H), 3.7-4.4 (rn, 2H), 5.4-5
．． 7(m,2H) Example 2 17@, 20-dimethyl-5-thiamer prostaglandin E, methyl ester 11.15-bis(t-butyldimethylsilyl)ether 29.7 g, 46
．． 3 mmol) and tetrakis(triphenylphosphine)palladium(0) (534rr@, 0.463r
tributyltin hydride (53 rmol) in a mixture of
, 9 g, 185 mmol) was added dropwise over 8 hours at room temperature. After the same post-treatment and separation and purification as in Example 1, 17
■, 20-dimethyl-5-thiabastaglandin E,
Methyl ester 11.15-bis(t-butyldimethylsilyl)ether (27.0g, 42.0mmol,
91%) obtained ONMR (δpp in CDC et al.)
: 0-0.2 (m, 12H), 0.87 (s, 18H),
0.7-1.1 (m, 6H).

1.1-3.0 (m, 27H), 3.62 (s, 3H)
, 3.8-4.3 (m.

2H), 5.4 to 5.6 (m, 2H) Example 3 17), 20-dimethyl-5-thiatoprostaglandin E1 methyl ester 11.15-bis(t-
Butyldimethylsilyl)ether (7.1g, 11
．． 09 mmol) and tetrakis(triphenylphosphine)palladium(0) (384111, 0.3
Tributyltin hydride (3 mmol) in a mixture of
19.4 g, 66.5 mmol) was added dropwise at room temperature over 6 hours. After the same post-treatment and separation and purification as in Example 1, 17g3), 20-dimethyl-5-thiaprostaglandin E, methyl ester 11.15-bis(t-butyldimethylsilyl)ether (6.35g, 9 .9
mmol, 89%) was obtained.

NMRCδ-In CDCJ, ): 0.2 (m, 12H) to O, 0.87 (s, 18H),
0.7-1.1 (m.

6H), 1.1-3. O(m, 27H), 3.63(s
, 3H), 3.8-4.3 (m, 2H), 5.4-5
．． 6(m, 2H) Example 4 17(8), 2G-dimethyl-5-thia Δ-prostaglandin E, methyl ester (1,20 g.

2.91 mmol) and tetrakis(triphenylphosphine)palladium(0) (1711K, 0.0
Tributyltin hydride (2.50 g, 8.6 mmol) in tetrahydrocufuran (3rd) solution
1) was added dropwise over a period of 48 hours. Extract with ethyl acetate according to Example 1, and perform separation in the same manner (20 g of silica gel; hexane:ethyl acetate 1:3) to obtain 1.
7■, 20-dimethyl-5-thiabuxtaglandin E
, methyl ester (1,00g.

2.42 mmol, 83%) was obtained.

NMR (δQ in CDCJ,): 0.9 (m, 6
H), 1.2 to 1-6 (m, 15H), 1.
111-2.8 (m.

10H), 3.67 (a, 3H), 4.1-4.2 (m
, 2B), 5.7 (m.

2H) Example 5 15-deoxy-16-hydroxy-16-methyl-Δ
? -Prostaglandin E1 methyl ester 11.16
-bis(t-butyldimethylsilinol ether (3,
72g, 5.85mmol) and tetrakis(triphenylphosphine)palladium(0) (68g, 0.
Tributyltin hydride (6.81 g, 23.4 mmol) was added dropwise to a mixed solution of 0.059 mmol 1 ) over 5 hours at room temperature. After post-treatment, separation and purification in the same manner as in Example 1, 15-deoxy-16-hydroxy-16-
Methyl prostaglandin E, methyl ester 11.1
6-His(1-butyldimethylsilyl)ether (3,
13g, 4.91nynol.

84%).

NMR (am in CDCj+,): 0 to 0.2 (
m, 12H), 0.86 (a, 18H), 0.7-1.
1 (m.

3M), 1.13 (s, 3H), 1.1-3.3 (m,
24M), 3.67 (s.

Claims (1)

[Claims] 1. The following formula [I] ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
......[I] In the formula, R^1 is a hydrogen atom, C_
1 to C_1_0 alkyl group, substituted or unsubstituted phenyl group, substituted or unsubstituted C_3 to C_1_0 cycloalkyl group, or substituted or unsubstituted phenyl (
C_1-C_2) represents an alkyl group, R^2, R^3
are the same or different, hydrogen atoms, tri(C_1 to C_
7) Represents a hydrocarbon silyl group or a group that forms an acetal bond with the oxygen atom of a hydroxyl group, R^4 represents a hydrogen atom, methyl group, or vinyl group, and R^5 may contain an oxygen atom Straight chain or branched chain C_3~
C_■alkyl group; optionally substituted phenyl group,
phenyl group or C_3-C_1_0 cycloalkyl group; or C_1-C_■ alkoxy group, optionally substituted phenyl group, phenoxy group, or C_3
~C_1_0 represents a straight or branched chain C_1 to C_5 alkyl group substituted with a cycloalkyl group, A represents a methylene group or a sulfur atom, and B represents a single bond or a methylene group. Display ■ is 7Z body, 7E body, or 7
It shows that Z-form and 7E-form coexist in arbitrary ratios. The following formula [II] is characterized by reducing the Δ^7-prostaglandin E_1 derivative represented by with an organic tin hydride compound in the presence of a zero-valent palladium catalyst. ▲There are mathematical formulas, chemical formulas, tables, etc.▼・・・・・・・・・
......[II] [In the formula, R^1, R^2, R^3
, R^4, R^5, A, and B are the same as defined above. ] A method for producing a prostaglandin E_1 derivative represented by: 2. Prostaglandin E_ according to claim 1, wherein the organotin hydride compound is tributyltin hydride.
1. Method for producing derivatives. 3. The method for producing a prostaglandin E_1 derivative according to claim 1 or 2, wherein the zero-valent palladium catalyst is tetrakis(triphenylphosphine)palladium(0). 4. The method for producing a prostaglandin E_1 derivative according to any one of claims 1 to 3, wherein R^1 is a hydrogen atom or an alkyl group of C_1 to C_1_0. 5. R^2 and R^3 are the same or different; hydrogen atom, tri(C_1-C_4) alkylsilyl group, diphenyl (C
_1 to C_4) alkylsilyl group, phenyldi(C_1
~C_4) Alkylsilyl group, 2-tetrahydropyranyl group, 2-tetrahydrofuranyl group, 1-ethoxyethyl group, 2-ethoxy-2-propyl group, (2-methoxyethoxy)methyl group, or 6,6-dimethyl group -3-oxa-2-oxobicyclo[3,1,0]hex-4-
A method for producing a prostaglandin E_1 derivative according to any one of claims 1 to 4, which is an yl group. 6. The method for producing a prostaglandin E_1 derivative according to any one of claims 1 to 5, wherein R^4 is a hydrogen atom. 7. The method for producing a prostaglandin E_1 derivative according to any one of claims 1 to 5, wherein R^4 is a methyl group. 8. The method for producing a prostaglandin E_1 derivative according to any one of claims 1 to 5, wherein R^4 is a vinyl group. 9, R^5 is a butyl group, a bentyl group, a hexyl group, 1-
Claim 1 which is a methylbutyl group, 1-methylbentyl group, 1-methylhexyl group, 2-methylbentyl group, 2-methylhexyl group, cyclobentyl group, cyclohexyl group, cyclohexylmethyl group, or phenyl group A method for producing a prostaglandin E_1 derivative according to any one of Items 1 to 8. 10. The method for producing a prostaglandin E_1 derivative according to any one of claims 1 to 9, wherein A is a methylene group. 11. Claims 1 to 9 in which A is a sulfur atom
A method for producing a prostaglandin E_1 derivative according to any one of paragraphs. 12. Claims 1 to 11 in which B is a single bond
A method for producing a prostaglandin E_1 derivative according to any one of paragraphs. 13. Prostaglandin E_1 according to any one of claims 1 to 11, wherein B is a methylene group.
Method for producing derivatives.